An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

Nikki A. Thiele, Victoria Brown, James M. Kelly, Alejandro Amor-Coarasa, Una Jermilova, Samantha N. MacMillan, Anastasia Nikolopoulou, Shashikanth Ponnala, Caterina F. Ramogida, Andrew K.H. Robertson, Cristina Rodríguez-Rodríguez, Paul Schaffer, Clarence Williams, John W. Babich, Valery Radchenko, Justin J. Wilson

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.

Original languageEnglish (US)
Pages (from-to)14712-14717
Number of pages6
JournalAngewandte Chemie - International Edition
Issue number46
StatePublished - Nov 13 2017
Externally publishedYes


  • actinium
  • cancer
  • chelates
  • macrocycles
  • radiopharmaceuticals

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry


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